Mass spectrometry has become the gold standard for the identification of proteins in proteomics. In this review, I will discuss the available literature on proteomic experiments that analyze human cerebrospinal fluid (CSF) and brain extra-cellular fluid (ECF), mostly obtained by cerebral microdialysis. Both materials are of high diagnostic value in clinical neurology, for example, in cerebrovascular disorders like stroke, neurodegenerative diseases like Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury and cerebral infectious and inflammatory disease, such as multiple sclerosis. Moreover, there are standard procedures,for sampling. In a number of studies in recent years, biomarkers have been proposed in CSF and ECF for improved diagnosis or to control therapy, based on proteomics and mass spectrometry. I will also discuss the needs for a transition of research-based experimental screening with mass spectrontery to fast and reliable diagnostic instrumentation for clinical use. (c) 2008 Wiley Periodicals, Inc., Mass Spec Rev 29:17-28, 2010